This Project has investigated the role of interstitial cells of Cajal (ICC) in GI motility for the past 14 years. This work has uncovered new hypotheses about the basic physiology of the spontaneous electrical rhythmicity of the GI tract and shown that: i ) ICC generate and propagate electrical slow waves, and ii) ICC mediate inputs from enteric motor neurons. The critical functions of these cells may be lost in a variety of human GI motility disorders in which lesions in ICC networks have been reported. In the next funding period we propose to further our studies of the rhythmic mechanisms of ICC and to specifically describe the function and molecular identity of the pacemaker conductance. We hypothesize that pacemaker current comes from the openings of voltage-independent, Ca2+ -inhibited, non-selective cation channels that may be of the TRP family of ion channels. We will also investigate how pacemaker activity is propagated within ICC networks by entraining the spontaneous activity of cellular pacemaker units. We hypothesize this is accomplished by voltage-dependent Ca 2+ entry, mainly through dihydropyridine-resistant Ca 2+ channels. Experiments are planned to investigate the function and molecular identity of this conductance. These studies will provide a mechanistic understanding of electrical rhythmicity in the GI tract and the tools to determine whether the functional units of rhythmicity in animal models are recapitulated in human gastrointestinal rhythmogenesis.